Sickle Cell Disease: Martin M Meremikwu

Blood and lymph disorders
..................................................
Sickle cell disease

Search date September 2007
Martin M Meremikwu
ABSTRACT
INTRODUCTION: Sickle cell disease causes chronic haemolytic anaemia, dactylitis, and painful acute crises, and increases the risk of
stroke, organ damage, bacterial infections, and complications of blood transfusion. In sub-Saharan Africa, up to a third of adults are carriers
of the defective sickle cell gene, and 1–2% of babies are born with the disease. METHODS AND OUTCOMES: We conducted a systematic
review and aimed to answer the following clinical questions: What are the effects of pharmaceutical and non-pharmaceutical interventions
to prevent sickle cell crisis and other acute complications in people with sickle cell disease? What are the effects of pharmaceutical and
non-pharmaceutical interventions to treat pain in people with sickle cell crisis? We searched: Medline, Embase, The Cochrane Library, and
other important databases up to September 2007 (Clinical Evidence reviews are updated periodically; please check our website for the most
up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA)
and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 38 systematic reviews, RCTs, or obser-
vational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS:
In this systematic review we present information relating to the effectiveness and safety of the following interventions: acupuncture, antibiotic
prophylaxis in children under 5 years of age, aspirin, avoidance of cold environment, blood transfusion, codeine, corticosteroid (with narcotic
analgesics), diflunisal, hydration, hydroxyurea, ibuprofen, ketorolac, limiting physical exercise, malaria chemoprophylaxis, morphine (controlled-
release oral after initial intravenous bolus, repeated intravenous doses), oxygen, paracetamol, patient-controlled analgesia, penicillin prophy-
laxis in children over 5 years of age, piracetam, pneumococcal vaccines, rehydration, and zinc sulphate.
QUESTIONS
What are the effects of non-pharmaceutical interventions to prevent sickle cell crisis and other acute complications
in people with sickle cell disease?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
What are the effects of pharmaceutical interventions to prevent sickle cell crisis and other acute complications in
people with sickle cell disease?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
What are the effects of non-pharmaceutical interventions to treat pain in people with sickle cell crisis?. . . . . . . 9
What are the effects of pharmaceutical interventions to treat pain in people with sickle cell crisis?. . . . . . . . . 11
INTERVENTIONS
SICKLE CELL CRISIS (NON-DRUG PREVENTION) SICKLE CELL PAIN (NON-DRUG TREATMENTS)
Trade off between benefits and harms Unknown effectiveness
Blood transfusion (prophylactic) for sickle cell crisis New Acupuncture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
.......................................... 4 Blood transfusion for sickle cell pain . . . . . . . . . . . . 10
Hydration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Unknown effectiveness
Oxygen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Avoidance of cold environment . . . . . . . . . . . . . . . . . 3
Limiting physical exercise . . . . . . . . . . . . . . . . . . . . . 4 SICKLE CELL PAIN (DRUG TREATMENTS)
Rehydration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Likely to be beneficial
Patient-controlled analgesia . . . . . . . . . . . . . . . . . . 11
SICKLE CELL CRISIS (DRUG PREVENTION)
Beneficial Trade off between benefits and harms
Antibiotic prophylaxis in children under 5 years of age Controlled-release oral morphine given after an initial
.......................................... 5 intravenous bolus dose of morphine versus repeated
doses of intravenous morphine . . . . . . . . . . . . . . . 15
Likely to be beneficial Corticosteroid as adjunct to narcotic analgesics . . 14
Hydroxyurea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Malaria chemoprophylaxis . . . . . . . . . . . . . . . . . . . . 7 Unknown effectiveness
Zinc sulphate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Aspirin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Codeine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Unknown effectiveness Diflunisal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Penicillin prophylaxis in children over 5 years of age . . Ibuprofen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
6
Ketorolac . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Piracetam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Paracetamol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Pneumococcal vaccines . . . . . . . . . . . . . . . . . . . . . . 9
Covered elsewhere in Clinical Evidence
NSAIDs
© BMJ Publishing Group Ltd 2009. All rights reserved. .................... 1 .................... Clinical Evidence 2009;03:2402
Sickle cell disease
To be covered in future updates Treatments for chronic complications of sickle cell dis-
Bone marrow transplantation ease
Treatment of chronic ulcers Treatments for sickle cell disease in pregnancy
Neonatal screening
Key points
• In sub-Saharan Africa, up to a third of adults are carriers of the defective sickle cell gene, and 1–2% of babies are
born with the disease.
Sickle cell disease causes chronic haemolytic anaemia, dactylitis, and painful acute crises, and increases the
risk of stroke, organ damage, bacterial infections, and complications of blood transfusion.
• We don’t know whether avoidance of cold environments, physical exercise, or dehydration can prevent crises or
complications in people with sickle cell disease.
Penicillin prophylaxis in children under 5 years of age reduces invasive pneumococcal infections regardless of
pneumococcal vaccination status. We don’t know whether penicillin prophylaxis is beneficial in older children.
Malaria chemoprophylaxis is considered useful in preventing malaria-induced crises, but we found few studies
evaluating its benefit.
• Hydroxyurea, piracetam, and zinc sulphate may reduce some complications of sickle cell disease, such as painful
crises, compared with placebo, but their long-term effects and safety are unknown.
• Morphine is widely used to treat severe pain, but we found no RCT evidence comparing it with placebo in people
with sickle cell crises.
Controlled-release oral morphine and patient-controlled analgesia may be as effective as repeated intravenous
doses of morphine. Oral morphine increases the risk of acute chest syndrome compared with intravenous admin-
istration.
High-dose corticosteroids may reduce the need for analgesia when added to intravenous morphine in people
with a sickle cell crisis, but may increase the risks of adverse effects such as infections, hypertension, and
metabolic problems.
• It is still unclear whether acupuncture, blood transfusion, hydration, oxygen, aspirin, codeine, diflunisal, ibuprofen,
ketorolac, or paracetamol reduce pain during sickle cell crisis.
DEFINITION Sickle cell disease refers to a group of disorders caused by inheritance of a pair of abnormal
haemoglobin genes, including the sickle cell gene. It is characterised by chronic haemolytic anaemia,
[1]
dactylitis, and acute episodic clinical events called “crises”. Vaso-occlusive (painful) crises are
the most common, and because of a resistance to nitric oxide, cause tissue ischaemia. Other crises
are acute chest syndrome, sequestration crisis, and aplastic crisis. A common variant of sickle cell
disease, also characterised by haemolytic anaemia, occurs in people with one sickle and one tha-
lassaemia gene. Sickle cell trait occurs in people with one sickle gene and one normal gene.
People with sickle cell trait have no clinical manifestation of illness. This review covers people with
sickle cell disease with or without thalassaemia.
[2]
INCIDENCE/ Sickle cell disease is most common in people living in or originating from sub-Saharan Africa.
PREVALENCE The disorder also affects people of Mediterranean, Caribbean, Middle-Eastern, and Asian origin.
The sickle cell gene is most common in areas where malaria is endemic — sickle cell trait affects
[3]
about 10–30% of Africa’s tropical populations. Sickle cell disease affects an estimated 1–2%
(120,000) of infants in Africa annually. About 178 babies (0.28/1000 conceptions) are affected by
[4] [4]
sickle cell disease in England annually. About 60,000 people in the USA and 10,000 in the
[5]
UK suffer from the disease.
AETIOLOGY/ Sickle cell disease is inherited as an autosomal recessive disorder. For a baby to be affected, both
RISK FACTORS parents must have the sickle cell gene. In parents with sickle cell trait, the risk of having an affected
baby is one in four for each pregnancy. Painful (vaso-occlusive) crisis is the most common feature
[6]
of the disease, and these episodes start in infancy and early childhood. Factors that precipitate
or modulate the occurrence of sickle cell crisis are not fully understood, but infections, hypoxia,
dehydration, acidosis, stress (such as major surgery or childbirth), and cold are believed to play
some role. In tropical Africa, malaria is the most common cause of anaemic and vaso-occlusive
[3]
crisis. High levels of fetal haemoglobin are known to ameliorate the severity and incidence of
sickle cell crisis and other complications of the disease.
PROGNOSIS People affected by sickle cell disease are predisposed to bacterial infections, especially those
caused by encapsulated organisms such as Pneumococcus, Haemophilus influenzae, Meningo-
© BMJ Publishing Group Ltd 2009. All rights reserved. ........................................................... 2

Sickle cell disease
coccus, and Salmonella species. Severe bacterial infections such as pneumonia, meningitis, and
[7]
septicaemia are common causes of morbidity and mortality, especially among young children.
About 10% of children with sickle cell anaemia may develop a stroke, and more than 50% of these
[8]
may suffer recurrent strokes. Abnormal features of cerebral blood vessels shown by transcranial
[9]
Doppler scan predict a high risk of stroke in children with sickle cell disease. Frequent episodes
of crisis, infections, and organ damage reduce the quality of life of people with sickle cell disease.
A high rate of vaso-occlusive (painful) crisis is an index of clinical severity that correlates with early
death. Life expectancy remains low, especially in communities with poor access to health services.
In some parts of Africa, about 50% of children with sickle cell disease die before their first birthday.
[3]
The average life expectancy with sickle cell disease in the USA is about 42 years for men, and
[10]
about 48 years for women. Frequent blood transfusions could increase the risk of immune re-
actions and infections, such as HIV and hepatitis B or C viruses, and Chagas’ disease. The need
for repeated blood transfusions in people with sickle cell disease predisposes them to the risk of
[11]
iron overload.
AIMS OF To reduce mortality, the incidence and severity of sickle cell crises, and other acute complications;
INTERVENTION to prevent organ damage; to improve quality of life and increase life expectancy; to achieve effective
pain relief during crises, with minimal adverse effects.
OUTCOMES Mortality; dactylitis, incidence of crisis; severity of crisis; incidence of other acute complications
(e.g. malaria, stroke, infectious complications [invasive pneumococcal infection or acute osteomyeli-
tis]); quality of life; adverse effects of treatment (e.g. gastrointestinal bleeding owing to NSAIDs,
addiction to narcotic analgesics, immune reactions, and infections caused by blood transfusions
[e.g. HIV, viral hepatitis, and Chagas’ disease]). Secondary outcomes include duration of crisis,
days out of school or work, and requirement for blood transfusion for severe anaemia. Fetal and
total haemoglobin levels are considered proxy outcomes and are not addressed in this review.
METHODS Clinical Evidence search and appraisal September 2007. The following databases were used to
identify studies for this review: Medline 1966 to September 2007, Embase 1980 to September
2007, and The Cochrane Database of Systematic Reviews 2007, Issue 3. Additional searches
were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for
all databases, Turning Research into Practice (TRIP), and NICE. Abstracts of the studies retrieved
were assessed independently by two information specialists using pre-determined criteria to iden-
tify relevant studies. Study design criteria for inclusion in this review were: published systematic
reviews and RCTs in any language and containing more than 20 individuals of whom more than
80% were followed up. Open studies were included. For the question on non-pharmaceutical inter-
ventions to prevent crisis and acute complications, a minimum length of follow-up of 1 year was
required. There was no minimum length of follow-up required to include studies for the other
questions. A search for published cohort studies was also undertaken for the avoidance of cold
environment and limiting physical exercise interventions, for the question on non-pharmaceutical
interventions to prevent crisis and acute complications. In addition, we use a regular surveillance
protocol to capture harms alerts from organisations such as the US FDA and the UK Medicines
and Healthcare products Regulatory Agency (MHRA), which are continually added to the review
as required. We have performed a GRADE evaluation of the quality of evidence for interventions
included in this review (see table, p 19 ). To aid readability of the numerical data in our reviews,
we round many percentages to the nearest whole number. Readers should be aware of this when
relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs).
QUESTION What are the effects of non-pharmaceutical interventions to prevent sickle cell crisis and
other acute complications in people with sickle cell disease?
OPTION AVOIDANCE OF COLD ENVIRONMENT. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
We found no direct information from RCTs or observational studies about the effects of avoiding exposure
to a cold environment on the prevention of sickle cell crisis and other life-threatening complications of
sickle cell disease.
For GRADE evaluation of other interventions for sickle cell disease see table, p 19 .
Benefits: We found no systematic review, RCTs, or observational studies of sufficient quality.
Harms: We found no RCTs or observational studies.
Comment: A 10-year retrospective study found a close correlation between cold weather and admissions for
[12]
painful sickle cell crisis. One observational study in 60 men with sickle cell disease and 30 adults

Sickle cell disease
with normal haemoglobin genotype found that vasoconstriction induced by skin cooling was signif-
icantly more likely to occur in people with sickle cell disease than in those with normal haemoglobin
genotype (83% in people with sickle cell disease v 60% in people with normal haemoglobin genotype;
[13]
P = 0.03). Among people with sickle cell disease, the frequency of painful crises was significantly
greater in those prone to cooling-induced vasoconstriction than in those less prone (0.36 crises/year
in people prone to cooling-induced vasoconstriction v 0.12 crises/year in people less prone to
[13]
cooling-induced vasoconstriction; P = 0.04).
OPTION LIMITING PHYSICAL EXERCISE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
We found no direct information from RCTs or observational studies about the effects of limiting exercise on
prevention of sickle cell crisis and other life-threatening complications of sickle cell disease.
Benefits: We found no systematic review, RCTs, or observational studies of sufficient quality.
Harms: We found no RCTs or observational studies.
Comment: Clinical guide:

Moderate exercise is generally accepted to be beneficial, especially in reducing the risk of cardio-
vascular disease. Moderate exercise is therefore unlikely to cause harm in people with sickle cell
disease. Strenuous exercise is suspected to lead to factors that may precipitate sickle cell crisis,
such as low tissue oxygen saturation, dehydration, and stress.
OPTION REHYDRATION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
We found no direct information from RCTs about the effects of increased fluid intake on the prevention of
sickle cell crisis.
Benefits: We found no systematic review or RCTs assessing increased fluid intake to prevent sickle cell
crisis.
Harms: We found no RCTs.
Comment: People with sickle cell disease are more prone to dehydration because of hyposthenuria (reduced
[14]
kidney ability to concentrate urine) leading to increased urine output. Because dehydration
leads to increased blood viscosity and acidosis with the likely consequence of sickling and vaso-
occlusion, increased fluid intake is routinely advocated for people with sickle cell disease.
OPTION BLOOD TRANSFUSION (PROPHYLACTIC) FOR SICKLE CELL CRISIS . . . . . . . . . . . . . New
Disease-related complications
Compared with standard care or no transfusion Blood transfusion given every 3–5 months is more effective at de-
creasing the incidence of stroke at 16–24 months in children at increased risk of stroke (high-quality evidence).
Mortality
Compared with standard care or no transfusion Blood transfusion given every 3–5 months is no more effective at
reducing mortality in children at increased risk of stroke (high-quality evidence).
Adverse effects
Blood transfusion has been associated with a high risk of iron overload and allo-immunisation, hypertensive or circu-
latory overload, febrile non-haemolytic reactions, allergic reactions, and haemolytic events.
For GRADE evaluation of interventions for sickle cell disease see table, p 19 .
[15]
Benefits: We found one systematic review (search date 2006, 2 RCTs, 209 people). The review found
that, compared with standard care or no transfusion, prophylactic blood transfusion given every
3–5 months significantly reduced the incidence of stroke at 16–24 months in children at increased
risk of stroke shown by abnormal transcranial Doppler scan (proportion who developed stroke:
1/101 [1%] with prophylactic transfusion v 13/108 [12%] with standard care; OR 0.10, 95% CI 0.02
to 0.58; P = 0.01). However, the review found no significant difference between groups in mortality
(1/209 [1%] with transfusion v 0/209 [0%] with standard care or no transfusion; OR 3.32, 95% CI
0.31 to 84.01; P = 0.5).

Sickle cell disease
[15]
Harms: The systematic review did not perform a meta-analysis for adverse effects. However, it reported
that the included trials found prophylactic transfusion was associated with high risk of iron overload
and allo-immunisation. One of the RCTs identified by the review reported that 10/63 (16%) children
in the blood transfusion group with sickle cell disease developed allo-immunisation, but no other
[16]
data were reported. The RCT also reported 15 other transfusion-related adverse effects, including
hypertension or circulatory overload (5 people), febrile non-haemolytic reactions (5 people), allergic
[16]
reactions (3 people), and haemolytic events (2 people). The review did not report data from
[15]
adverse effects in the usual-care control group of the trial.
Another RCT included in the review also reported that iron overload developed faster than antici-
pated in the transfusion group, with mean serum ferritin levels rising from 164 ng/mL to 1804 ng/mL
at 12 months, and to 2509 ng/mL at 24 months. The RCT did not report data for the control group.
The RCT also found a new case (out of 35 people) of allo-immunisation in one person continuing
[17]
transfusion, compared with no new cases in the discontinued transfusion group. Although
transmission of blood-borne infections is a widely recognised risk of a blood transfusion, none of
the people involved in the reported trials acquired such infections.
Comment: None.
QUESTION What are the effects of pharmaceutical interventions to prevent sickle cell crisis and other
acute complications in people with sickle cell disease?
OPTION ANTIBIOTIC PROPHYLAXIS IN CHILDREN UNDER 5 YEARS OF AGE. . . . . . . . . . . . . . . . . . .
Penicillin compared with placebo Penicillin prophylaxis is more effective at reducing the risk of invasive pneumococcal
infections in children aged under 5 years with sickle cell disease. This beneficial effect is seen in children irrespective
of their vaccination status (high-quality evidence).
Mortality
Penicillin compared with placebo Penicillin prophylaxis seems to be no more effective at reducing mortality in children
aged under 5 years with sickle cell disease (moderate-quality evidence).
Benefits: We found one systematic review (search date 2005, 2 RCTs, 857 children with sickle cell anaemia)
[18]
The RCTs identified by the review compared penicillin versus no penicillin or placebo. The review
found that penicillin prophylaxis caused a small but significant reduction in the risk of pneumococcal
infections, regardless of vaccination status, compared with no penicillin or placebo (9/248 [4%]
with penicillin prophylaxis v 19/209 [9%] without penicillin prophylaxis; RR 0.39, 95% CI 0.17 to
0.88). It found no significant difference in mortality between penicillin and no penicillin (0/105 [0%]
with penicillin prophylaxis v 4/110 [4%] without penicillin prophylaxis; RR 0.12, 95% CI 0.01 to
[18]
2.14). The wide confidence interval in the assessment of mortality suggests that the RCTs may
have been underpowered to detect a difference in mortality.
The first RCT included in the review (242 children in Jamaica, aged 6–36 months) had a factorial
design, and compared monthly intramuscular penicillin injection (dose not reported) versus no in-
jection. Half of the children receiving penicillin and half of those not receiving penicillin also received
either polysaccharide pneumococcal vaccine or Haemophilus influenza vaccine. The second RCT
(215 children in the USA, aged 3–36 months) compared oral penicillin 125 mg twice daily versus
placebo. All children received polysaccharide pneumococcal vaccine at 1 and 2 years of age. The
RCT was discontinued earlier than planned because of a highly significant reduction in the risk of
pneumococcal infection in the penicillin group compared with the no penicillin group (RR 0.16, 95%
[18]
CI 0.04 to 0.70), making it unethical to continue recruitment.
Harms: One RCT identified by the review found minor adverse effects, including localised reactions to
vaccine, and nausea and vomiting (3 cases); the difference in nausea and vomiting between
penicillin prophylaxis and placebo was not significant (2/210 [0.95%] with penicillin prophylaxis v
[18]
1/199 [0.50%] without penicillin prophylaxis; RR 1.90, 95% CI 0.17 to 20.74).
Comment: Clinical guide: Antibiotic prophylaxis and pneumococcal vaccines are recommended to reduce
morbidity and mortality from pneumococcal infections in vulnerable groups, including children with
[19]
sickle cell disease. The effectiveness of antibiotic prophylaxis could be diminished by a high
incidence of Streptococcus pneumoniae resistance. Allergy to penicillin is a contraindication. Ery-

Sickle cell disease
thromycin is usually the recommended alternative to penicillin, but its value in sickle cell disease
has not been evaluated in an RCT.
OPTION ANTIBIOTIC PROPHYLAXIS IN CHILDREN OVER 5 YEARS OF AGE. . . . . . . . . . . . . . . . . . . .
Penicillin compared with placebo Continuing penicillin prophylaxis for 2 years in children aged over 5 years seems
to be no more effective at reducing the risk of pneumococcal infections (moderate-quality evidence).
Mortality
Penicillin compared with placebo Continuing penicillin prophylaxis for 2 years in children aged over 5 years with
sickle cell disease seems to be no more effective at reducing mortality (moderate-quality evidence).
[18]
Benefits: We found one systematic review (search date 2005), which identified one RCT (400 children,
aged 5 years) comparing continuing penicillin prophylaxis after the age of 5 years versus placebo.
[20]
All of the children had received prophylactic penicillin for 2 years and polysaccharide pneumo-
coccal vaccine at age 2–3 years. The RCT found no significant difference between continuing
penicillin 125 mg twice daily and placebo in the risk of pneumococcal infections (RR 0.47, 95% CI
0.09 to 2.56) or mortality (RR 0.99, 95% CI 0.14 to 7.08).
Harms: The RCT reported nausea and vomiting both with penicillin and with placebo (nausea and vomiting:
2/201 [1.0%] with penicillin v 1/199 [0.5%] with placebo; significance not assessed). Local pain
from the polysaccharide pneumococcal vaccine was also reported in two children. No serious ad-
[20]
verse events were reported.

See clinical guide in antibiotic prophylaxis in children under 5 years of age, p 5 above.
OPTION HYDROXYUREA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Incidence of crises
Compared with placebo Hydroxyurea is more effective at reducing the incidence of crises at 21 months in adults
with sickle cell disease (high-quality evidence).
Compared with placebo Hydroxyurea seems to be more effective at reducing the risk of acute chest syndrome but
seems to be no more effective at reducing the risk of stroke or hepatic sequestration in adults with sickle cell disease
(moderate-quality evidence).
Mortality
Compared with placebo Hydroxyurea seems to be no more effective at reducing mortality in adults with sickle cell
disease (moderate-quality evidence).
Quality of life
Compared with placebo Hydroxyurea seems to be no more effective at improving quality of life at 12 months in adults
with sickle cell disease (moderate-quality evidence).
Adverse effects
Hydroxyurea has been associated with neutropenia, hair loss, skin rash, and gastrointestinal disturbances. We found
no direct information from RCTs about the long-term effects of hydroxyurea.
Benefits: Hydroxyurea versus placebo:

[21]
We found one systematic review (search date 2005, 2 RCTs). Both of the included RCTs
[22]
compared hydroxyurea versus placebo (25 children, crossover design; 299 adults, parallel group
[23]
design ).
Incidence of crises:
The review found that hydroxyurea significantly reduced the number of crises in adults compared
with placebo after a mean follow-up of 21 months (1 RCT, 299 adults, mean number of episodes
during follow-up: 5.1 with hydroxyurea v 7.9 with placebo; WMD –2.80, 95% CI –4.74 to –0.86).
[21]
It also found that, over 6 months, children taking hydroxyurea had shorter hospital stays before
crossover than children taking placebo (1 RCT, 25 children, mean duration of hospital stay: 5.3
[22]
days with hydroxyurea v 15.2 days with placebo; CI not reported).
Sickle cell disease
Disease-related complications:
The review identified one RCT (299 adults), which found that hydroxyurea significantly reduced
the risk of acute chest syndrome (RR 0.44, 95% CI 0.28 to 0.68) and the need for blood transfusion
[21]
(RR 0.67, 95% CI 0.52 to 0.87) compared with placebo. It found no significant difference between
hydroxyurea and placebo in stroke (RR 0.64, 95% CI 0.11 to 3.80) or hepatic sequestration (RR
0.32, 95% CI 0.03 to 3.06) — although fewer people taking hydroxyurea had these outcomes, and
the RCT lacked power to detect a clinically important difference.
Mortality:
The review identified one RCT (299 adults), which found no significant difference between hydrox-
yurea compared with placebo in mortality related to sickle cell disease (RR 0.48, 95% CI 0.09 to
2.60) — although fewer people taking hydroxyurea had these outcomes, and the RCT lacked
[21]
power to detect a clinically important difference between groups.
Quality of life:
The RCT (299 adults) identified by the review reported quality-of-life data collected at 6-monthly
[21]
intervals using the Health Status Survey, Profile of Mood States, and the Ladder of Life. Lower
scores reflected lower quality of life in all scales. It found no significant difference between hydrox-
yurea and placebo in quality of life, although changes from baseline on all quality-of-life scales at
12 months were higher with hydroxyurea than with placebo (general health perception: WMD +0.60,
95% CI –0.18 to +1.38; social function: WMD +0.20, 95% CI –0.36 to +0.76; pain recall: WMD
+0.40, 95% CI –0.18 to +0.98; and Ladder of Life: WMD +0.40, 95% CI –0.15 to +0.95).
9
Harms: Neutropenia (neutrophil count 2500 x 10 /L or less) was reported in 79% of people in the hydrox-
yurea group compared with 37% of people allocated to placebo, but no infection was related to
neutropenia. Some people suffered hair loss, skin rash, and gastrointestinal disturbances, but these
[21]
did not differ significantly between the groups. The long-term safety of hydroxyurea in sickle
cell disease remains uncertain.
Comment: In the RCT in adults, hydroxyurea was given at 15 mg/kg daily, and the dose increased at 12-
weekly intervals by 2.5 mg/kg daily until mild bone marrow suppression was detected (indicated
3 3
by a neutrophil count of less than 2000/mm , a reticulocyte or platelet count of less than 80,000/mm ,
[23]
or a haemoglobin level of less than 4.5 g/dL). The dose in children was 20 mg/kg daily and in-
[22]
creased to a maximum of 25 mg/kg daily. There is a need for further good-quality RCTs assessing
the long-term safety of hydroxyurea.
OPTION MALARIA CHEMOPROPHYLAXIS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Incidence of crises
Compared with placebo Malaria chemoprophylaxis using proguanil or pyrimethamine seems to be more effective at
reducing sickle cell crises in children (moderate-quality evidence).
Compared with placebo Malaria chemoprophylaxis using proguanil or pyrimethamine seems to be no more effective
at reducing malaria infections in children (moderate-quality evidence).
Malaria chemoprophylaxis plus antibiotics compared with placebo Malaria chemoprophylaxis with chloroquine plus
antibiotics may be more effective at reducing the incidence of malaria in areas without chloroquine resistance, but
may be no more effective at reducing dactylitis (very low-quality evidence).
Note
Plasmodium falciparum malaria is believed to precipitate sickle cell crisis and to increase the risk of death in children
with sickle cell anaemia. Regular chemoprophylaxis with antimalarial drugs is therefore advocated by consensus.
Benefits: Malaria chemoprophylaxis versus placebo:

We found one systematic review (search date 2006, 1 RCT, 97 children, 1 quasi-randomised trial,
[24]
126 children). The RCT identified by the review found that malaria chemoprophylaxis (proguanil
or pyrimethamine) significantly reduced sickle cell crises compared with placebo (proportion with
crisis: 2/68 [3%] with chemoprophylaxis v 5/29 [17%] with placebo; RR 0.17, 95% CI 0.04 to 0.83).
It also found that chemoprophylaxis significantly reduced hospital admissions (7/68 [10%] with
chemoprophylaxis v 11/29 [40%] with placebo; RR 0.27, 95% CI 0.12 to 0.63) and blood transfusions
(3/68 [4%] with chemoprophylaxis v 8/29 [27%] with placebo; RR 0.16, 95% CI 0.05 to 0.56). It
found no significant difference between chemoprophylaxis and placebo in rates of malaria infection
(19/68 [28%] with chemoprophylaxis v 9/29 [31%] with placebo; RR 0.90, 95% CI 0.46 to 1.75).

Sickle cell disease
Malaria chemoprophylaxis plus antibiotic versus placebo:
The quasi-randomised trial identified by the review compared weekly malaria chemoprophylaxis
using chloroquine plus antibiotic prophylaxis using a monthly injection of long-acting benzathine
[24]
penicillin versus sterile water. It found that malaria chemoprophylaxis plus antibiotics significantly
reduced the incidence of malaria compared with sterile water (5/73 [7%] with chemoprophylaxis v
36/84 [43%] with sterile water; RR 0.16, 95% CI 0.07 to 0.39). It found no significant difference in
dactylitis between malaria chemoprophylaxis plus antibiotics and sterile water (P less than 0.1; no
[24]
further data reported).
[24]
Harms: The RCTs identified by the review gave no information on adverse effects. The adverse effects
of drugs commonly used for malaria prophylaxis (chloroquine, proguanil, doxycycline, mefloquine,
and atovaquone–proguanil) are described elsewhere (see review on malaria: prevention in travellers).
Comment: Inadequate allocation concealment and poor randomisation technique limit the validity of the results
[24]
of the quasi-randomised trial identified by the review. The RCT was performed between 1962
and 1964, at a time when chloroquine-resistant P falciparum was not as widespread as it is today.
Clinical guide:
Using chloroquine for malaria chemoprophylaxis in areas where chloroquine resistance is known
to be high is unlikely to be effective. Because P falciparum malaria is believed to precipitate sickle
cell crisis and increase the risk of death in children with sickle cell anaemia, regular chemoprophy-
[3]
laxis with antimalarial drugs is advocated by consensus.
OPTION PIRACETAM. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Incidence of crises
Compared with placebo We don’t know whether piracetam is more effective at reducing the incidence of sickle cell
crises in children at 8–12 weeks (very low-quality evidence).
Benefits: We found one systematic review (search date 2007, 3 RCTs, 169 children) comparing orally ad-
[25]
ministered piracetam versus placebo or standard care in people with sickle cell disease. The
review did not pool data owing to poor reporting of the included trials. One of the RCTs identified
by the review (13 children aged 4–15 years) found that piracetam significantly reduced the incidence
of sickle cell crisis compared with placebo (average number of crises per month per patient: 0.89
[26]
with piracetam v 1.85 with placebo; P less than 0.05). The review reported that the two other
[25]
RCTs did not confirm these findings, but no data were reported for these trials in the review.
Insufficient data were reported to make conclusions regarding other clinical outcomes.
[26] [25]
Harms: One crossover trial identified by the review reported that one child out of the 13 enrolled
experienced dizziness during the piracetam phase. No children in the placebo group reported
dizziness. It is uncertain whether this adverse effect occurred before or after crossover, or during
[26]
both periods of the trial. The other RCTs identified by the systematic review reported no infor-
mation on adverse effects.

Since there are insufficient data on the effectiveness or safety of piracetam in people with sickle
cell disease, more reliable data are needed before giving it to people with sickle cell disease.
OPTION ZINC SULPHATE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Incidence of crises
Compared with placebo Zinc sulphate may be more effective at reducing the incidence of sickle cell crises in children
with sickle cell disease (low-quality evidence).
[27]
Benefits: We found one systematic review (search date 2006, 1 RCT, 145 children aged 12–17 years).
The RCT identified by the review found that zinc sulphate (200 mg 3 times daily, duration of treatment
not reported) significantly reduced the mean number of sickle cell crises (including vaso-occlusive,
haemolytic, sequestration, and aplastic crisis) compared with placebo (mean: 2.46 with zinc sulphate
v 5.29 with placebo; WMD –2.83; 95% CI –3.51 to –2.15). No deaths occurred in either group.
Harms: The RCT identified by the review stated that “no significant toxicity” associated with zinc sulphate
[27]
was observed, although it was unclear which adverse effects were monitored.

Sickle cell disease
The number of participants involved in the included RCT was small. As small RCTs may overestimate
the effects of an intervention, it would be appropriate to wait for larger RCTs to confirm the observed
effects before giving zinc sulphate routinely to people with sickle cell disease for the purpose of
preventing crisis.
OPTION PNEUMOCOCCAL VACCINES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Polysaccharide pneumococcal vaccine compared with control Polysaccharide pneumococcal vaccine is no more
effective at reducing the incidence of pneumococcal infections in people with sickle cell disease (high-quality evidence).
Adverse effects
Both polysaccharide pneumococcal and conjugate pneumococcal vaccines have been associated with mild fever,
local pain, and swelling, but are not known to cause severe adverse effects.
Benefits: Polysaccharide pneumococcal vaccine versus placebo:

[28]
We found one systematic review (search date 2004, 1 RCT, 242 people). One RCT identified
by the systematic review found no significant difference in the incidence of pneumococcal infection
between polysaccharide pneumococcal vaccination and placebo (AR: 11/159 [7%] with vaccination
[28]
v 2/83 [2%] with placebo; RR 2.87, 95% CI 0.65 to 12.65).
Pneumococcal conjugate vaccine versus placebo:

Three RCTs of pneumococcal conjugate vaccines were identified by the review, but did not assess
[28]
clinical outcomes, such as incidence of pneumococcal infections.
Harms: The systematic review found no severe adverse events with either polysaccharide pneumococcal
or pneumococcal conjugate vaccines, but both were associated with mild fever, local pain, and
[28]
swelling.

Antibiotic prophylaxis and pneumococcal vaccines are recommended to reduce morbidity and
mortality from pneumococcal infections in vulnerable groups, including children with sickle cell
[19]
disease. An increase in penicillin-resistant strains of Streptococcus pneumoniae has highlighted
the potential for pneumococcal vaccination as an alternative to antibiotics. Polyvalent polysaccharide
pneumococcal vaccine offers no protective immunity to children under 2 years of age, who have
[19]
the highest rates of invasive pneumococcal infections. Pneumococcal conjugate vaccines have
been reported to have protective efficacy in children under 2 years of age, and are recommended
for routine use in young children. However, this protective effect has not been shown in infants
[29]
with sickle cell disease.
QUESTION What are the effects of non-pharmaceutical interventions to treat pain in people with sickle
cell crisis?
OPTION ACUPUNCTURE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
We found no direct information from RCTs about the effects of acupuncture on pain in people with sickle
cell disease.
Benefits: We found no systematic review or RCTs.
Harms: Acupuncture is widely used to relieve pain. Adverse effects of acupuncture in different populations
are discussed in other Clinical Evidence reviews (see reviews on acute low back pain and chronic
low back pain).
Comment: None.
OPTION HYDRATION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
We found no direct information from RCTs about the effects of routinely giving extra fluids to reduce pain
in people with sickle cell crises without dehydration.

Sickle cell disease
Benefits: We found one systematic review (search date 2007), which identified no RCTs of sufficient quality
[30]
assessing hydration in people with sickle cell disease.
[30]

It is standard practice to give extra intravenous or oral fluids to dehydrated patients. This widely
accepted clinical practice also applies to people with sickle cell disease who are dehydrated.
However, it is unclear whether giving extra fluids routinely to people with painful sickle cell crisis
without dehydration will be beneficial or harmful.
OPTION OXYGEN. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Symptom severity (pain)

Compared with air We don’t know whether oxygen given as an adjunct to continuous intravenous morphine is more
effective at reducing pain or at reducing the progression of crises (appearance of new pain sites) in people with vaso-
occlusive crisis (low-quality evidence).
Benefits: Oxygen versus air:

We found no systematic review. One RCT (25 children and adolescents, aged 3–18 years with
vaso-occlusive crisis) compared 50% oxygen versus air as an adjunct to continuous intravenous
[31]
morphine infusion. It found no significant difference in the duration of severe pain (0.94 days
with 50% oxygen v 0.95 days with air; WMD –0.19 days, 95% CI –0.91 days to +0.89 days), amount
of narcotic analgesic given, or further admission to hospital for pain (reported as non-significant
for all outcomes, CI not reported). It also found no significant difference in the proportion of people
with progression of crisis, indicated by the appearance of new pain sites (5/14 [36%] with 50%
oxygen v 4/11 [36%] with air; reported as not significant, CI not reported). The RCT may have
lacked power to detect a clinically important difference between interventions.
Harms: Oxygen versus air:

[31]
The RCT gave no information about adverse effects associated with oxygen treatment.
[31] [32]
Comment: The RCT was reported in two publications.
Clinical guide:
Low tissue-oxygen saturation is a dominant factor in the mechanism that results in sickling. Given
that increased sickling is a key component of the pathophysiology of vaso-occlusive crisis and
acute chest syndrome, oxygen treatment is expected to ameliorate these conditions. Oxygen
treatment is recommended routinely for treatment of sickle cell acute chest syndrome, but people
[31]
with acute chest syndrome were excluded from the RCT.
OPTION BLOOD TRANSFUSION FOR SICKLE CELL PAIN. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
We found no direct information from RCTs about blood transfusions in the treatment of pain in sickle cell
crisis.
Benefits: We found no systematic review or RCTs assessing blood transfusion to treat pain in sickle cell
crisis.
Comment: A systematic review showed (from limited evidence) that conservative pre-operative blood transfusion
is as effective as aggressive transfusion in reducing the incidence of peri-operative complications
[33]
in sickle cell disease.
Clinical guide:
Repeated (chronic) blood transfusions are given to prevent severe complications of sickle cell
disease, notably acute chest syndrome, sequestration crisis, and stroke, with some limited evidence
[34] [35]
of benefits. Blood transfusion is also used to treat acute chest syndrome of sickle cell disease
[34] [36]
with the aim of reducing the course of illness and risk of death. These interventions are
associated with variable degrees of adverse events from repeated blood transfusions, such as in-
© BMJ Publishing Group Ltd 2009. All rights reserved. .......................................................... 10
Sickle cell disease
fections, iron-overload, allo-immunisation, and blood transfusion reactions (including delayed
[14] [37]
transfusion reactions and hyper-haemolytic syndrome). Decisions to use blood transfusion
to treat or prevent any of the complications of sickle cell disease should take into account the need
to balance benefits with harms.
QUESTION What are the effects of pharmaceutical interventions to treat pain in people with sickle cell
crisis?
OPTION PATIENT-CONTROLLED ANALGESIA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Patient-controlled pethidine compared with intermittently administered pethidine We don’t know whether patient-
controlled analgesia with pethidine is more effective at reducing pain at 3 days in adults with sickle cell crisis (low-
quality evidence).
Patient-controlled morphine compared with intermittently administered morphine Patient-controlled analgesia with
high-dose and low-dose morphine may be no more effective at reducing pain in adults with sickle cell crisis (low-
quality evidence).
Benefits: Patient-controlled pethidine versus intermittently administered pethidine:

We found no systematic review. One RCT (20 adults, aged 17–39 years) compared patient-controlled
analgesia (infusion of pethidine 25–30 mg/hour plus oral hydroxyzine 50 mg every 6 hours) versus
intermittent intramuscular analgesia (im pethidine 75–100 mg plus im hydroxyzine 50–75 mg given
[38]
as necessary every 3–4 hours). It found no significant difference between patient-controlled
and intermittent analgesia in pain over 3 days, as measured by categorical and analogue pain
scales (categorical scores on day 2: WMD +4.00 mm, 95% CI –1.09 mm to +9.09 mm; analogue
scores: WMD +68.00 mm, 95% CI –25.35 mm to +161.35 mm). It also found no significant difference
in the amount of pethidine used each day after 3 days (WMD +451 mg, 95% CI –70 mg to +972 mg).
The units being measured in the pain scales were not defined.
Patient-controlled morphine versus intermittently administered morphine:

One RCT compared patient-controlled analgesia with morphine versus intermittent intravenous
injections of morphine in two phases of high- and low-dose regimen in adults with sickle cell crisis
[39]
pain. In the first phase (20 people), the intermittent treatment group received a 4 mg intravenous
bolus of morphine sulphate every 30–60 minutes as needed to achieve a linear analogue pain in-
tensity score of less than 50 mm. The patient-controlled analgesia group received a 2 mg bolus of
intravenous morphine sulphate followed by a 1 mg intravenous bolus controlled by the patient, with
a 6-minute lockout. If pain control by the end of the first 30 minutes was inadequate (pain score
less than 50 mm), the dose of morphine was increased to 6 mg for the intermittent treatment group,
and to 1.5 mg for the patient-controlled analgesia group. The second phase (25 people) was similar,
but used higher doses of morphine for the patient-controlled analgesia group (2.7 mg with a 10-
minute lockout) and the intermittent treatment group (8 mg every 30–60 minutes). The RCT found
a reduction in pain scores on the linear analogue scale in both groups, with no significant difference
between treatment groups in both the first phase (WMD –0.10 mm, 95% CI –27.03 mm to
+26.83 mm) and the second phase (WMD +9.00 mm, 95% CI –18.25 mm to +36.25 mm). It found
no significant difference in the total amount of morphine given between patient-controlled analgesia
and intermittent intravenous analgesia in the first phase (WMD –6.70 mg, 95% CI –23.35 mg to
+9.95 mg) or the second phase of the study (WMD +6.40 mg, 95% CI –8.71 mg to +12.51 mg).
Harms: Patient-controlled pethidine versus intermittently administered pethidine:

[38]
The RCT gave no information on adverse effects. Severe adverse effects such as seizures and
[40]
respiratory depression have been associated with pethidine. There are concerns about possible
addiction to narcotic analgesics, but some studies show a relatively low rate of addiction (0–11%)
[41]
in people with sickle cell disease.
Patient-controlled morphine versus intermittently administered morphine:

The RCT found that nausea, vomiting, and pruritus were common events observed with both high-
and low-dose morphine, with 44% requiring anti-emetic treatment (prochlorperazine) in the inter-
mittent treatment group, and 31% requiring anti-emetic treatment in the patient-controlled analgesia
[39]
group. The RCT found a non-significant difference in the proportion of people who had adverse
effects (53% with patient-controlled analgesia v 47% with intermittent intermittent intravenous
analgesia; P = 0.715), but no details were given about the types of adverse effects or their severity.
Neither respiratory depression nor clinically significant hypotension was observed during the RCT.
Respiratory depression is a well-known adverse effect of narcotic drugs.

Sickle cell disease
Comment: None.
OPTION ASPIRIN. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
We found no direct information from RCTs about the effects of aspirin on pain in people with sickle cell
disease.

Aspirin is widely used by clinicians to relieve mild pain and fever. There is concern about its use
in children as it has been associated with Reye’s syndrome. The adverse effects of aspirin in dif-
ferent populations are discussed in other Clinical Evidence reviews (see reviews on stroke prevention
and NSAIDs). Studies on long-term aspirin prophylaxis address a different question on treating
acute pain in sickle cell crisis to those here.
OPTION CODEINE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
We found no direct information from RCTs about the effects of codeine on pain in people with sickle cell
disease.
Harms: Codeine is widely used by clinicians to relieve moderate pain. Prolonged use of narcotic analgesics
may lead to addiction. Codeine is known to be less addictive than other narcotic analgesics, such
as morphine and pethidine.
Comment: None.
OPTION DIFLUNISAL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Compared with placebo We don’t know whether diflunisal added to intramuscular pethidine regimens is more effective
at reducing pain in people with vaso-occlusive sickle cell crisis (very low-quality evidence).
Benefits: Oral diflunisal versus placebo:

We found one systematic review (search date 2002, 1 RCT, including 37 adults with sickle cell
[42]
disease) comparing diflunisal versus placebo. The RCT (37 adults, 32 having 46 episodes of
vaso-occlusive crisis) compared oral diflunisal (22 adults 1000 mg loading dose followed by 500 mg
[43]
every 12 hours for 5 days) versus placebo (15 adults). Intravenous pethidine 1.0–1.5 mg/kg
and hydroxyzine 0.5–1.0 mg/kg were given every 3–4 hours as necessary for pain relief in all
people. A categorical pain scale ranging from 0 to 5 was used to assess the response to treatment.
The RCT found no significant difference in pain intensity scores between adding diflunisal and
adding placebo (P reported as non-significant, CI not reported). It also found no significant difference
in the mean total dose of pethidine given (1400 mg with diflunisal v 1000 mg with placebo; WMD
+400.0, 95% CI –28.6 to +828.6). The RCT is likely to have lacked power to detect a clinically im-
portant difference between treatments.
Harms: Oral diflunisal versus placebo:

The RCT found that diflunisal significantly increased nausea compared with placebo (6/22 [27%]
[43]
with diflunisal v 2/15 [13%] with placebo; P less than 0.05). One person discontinued diflunisal
because of a facial rash. Adverse events associated with NSAIDs have been reviewed elsewhere
in Clinical Evidence (see reviews on NSAIDs,acute low back pain, chronic low back pain,osteoarthri-
tis of the knee,tennis elbow, and dysmenorrhoea).
Comment: The RCT used pain scales as the basis of randomised allocation. This method of randomisation
may introduce bias.

Sickle cell disease
OPTION IBUPROFEN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
We found no direct information from RCTs about the effects of ibuprofen on pain in people with sickle cell
disease.
Harms: Ibuprofen is widely used by clinicians to relieve mild pain and fever. The adverse effects of
ibuprofen in other populations are discussed in other Clinical Evidence reviews (see reviews on
AOM, carpal tunnel syndrome, and migraine headache).
Comment: Adverse events associated with NSAIDs have been reviewed elsewhere in Clinical Evidence (see
reviews on NSAIDs, acute low back pain, chronic low back pain, osteoarthritis of the hip, osteoarthri-
tis of the knee, tennis elbow, and dysmenorrhoea).
OPTION KETOROLAC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Compared with pethidine We don’t know whether ketorolac is more effective at 150 minutes at reducing pain in
people with vaso-occlusive sickle cell crisis (very low-quality evidence).
Ketorolac plus pethidine compared with placebo plus pethidine We don’t know whether intravenous ketorolac given
as a supplement to pethidine is more effective at reducing pain in people with vaso-occlusive sickle cell crisis (very
low-quality evidence).
Ketorolac plus morphine sulphate compared with placebo plus morphine sulphate We don’t know whether intravenous
ketorolac plus parenteral morphine sulphate is more effective at reducing pain in people with vaso-occlusive sickle
cell crisis (low-quality evidence).
[42]
Benefits: We found one systematic review (search date 2002, 4 RCTs, 88 people) which identified four
[44] [45] [46] [47]
small RCTs comparing ketorolac versus placebo or other drugs. The review could
not perform a meta-analysis owing to heterogeneity of the RCTs identified; individual RCTs are
reported below.
Ketorolac versus pethidine:

One crossover RCT (20 adolescents, aged 11–19 years) compared parenteral ketorolac 1.0 mg/kg
versus parenteral pethidine 1.5 mg/kg in sickle cell vaso-occlusive crisis in the first phase (150
[44]
minutes) before crossover. Pain was measured in a visual analogue scale (VAS) ranging from
0 mm to 80 mm, where 0 mm denotes “no pain” and 80 mm denotes “the worst pain I’ve ever had”.
Measurements were taken at 30 and 150 minutes. It found that ketorolac significantly reduced pain
compared with pethidine at 30 minutes (mean VAS: 39 mm with ketorolac v 54 mm with pethidine;
P less than 0.01) and 150 minutes (mean VAS: 33 mm with ketorolac v 56 mm with pethidine; P
less than 0.01). It found no significant difference between ketorolac and pethidine in the proportion
of people who were pain free at 150 minutes (4/10 [40%] with ketorolac v 2/10 [20%] with pethidine;
RR 2.00, 95% CI 0.47 to 8.56), but the RCT lacked power to detect clinically important differences.
Data obtained after crossover were not included, because the process of crossover is deemed
unsuitable to confirm the effect of either drug.
Ketorolac plus pethidine versus placebo plus pethidine:

[45] [46]
We found two RCTs. The first RCT (18 adults with vaso-occlusive sickle cell crisis) found
no significant difference in pain between a single dose of intramuscular ketorolac 60 mg and
placebo given as a supplement to repeated doses of intravenous pethidine (mean pain score as-
[45]
sessed by VAS: 44 with ketorolac v 37 with placebo; P = 0.49). The second RCT (21 people
with sickle cell crisis, over 14 years of age) compared intravenous infusion of ketorolac (150 mg
on the first day, 120 mg on subsequent days for a total of 5 days) versus placebo as a supplement
[46]
to intermittent intramuscular pethidine (100 mg every 3 hours for moderate or severe pain). It
found that people taking intravenous ketorolac required a significantly lower amount of pethidine
to control pain compared with placebo (WMD –937.8 mg of pethidine, 95% CI –1803.2 mg to
–72.4 mg).
Ketorolac plus morphine sulphate versus placebo plus morphine sulphate:

One RCT (29 people, 41 episodes of vaso-occlusive sickle cell crisis, aged 5–17 years) compared
intravenous ketorolac 0.9 mg/kg versus placebo as a supplement to simultaneous treatment with
Sickle cell disease
[47]
parenteral morphine sulphate 0.1 mg/kg. Morphine was repeated every 2 hours based on pain
intensity rated on the VAS. Pain episodes were the basis for randomisation. The RCT found no
significant difference in the need for morphine between ketorolac and placebo (0.28 mg/kg with
ketorolac v 0.32 mg/kg with placebo; WMD –0.04 mg/kg, 95% CI –0.09 mg/kg to +0.01 mg/kg). It
also found no significant difference between ketorolac and placebo in the proportion of people re-
quiring admission for further management of severe pain (9/22 [41%] with ketorolac v 10/19 [53%]
with placebo; RR 0.78, 95% CI 0.40 to 1.50).
Harms: No severe adverse events were reported in the RCTs, apart from one case of epistaxis in a person
[46]
who received ketorolac. Other adverse events (mostly gastrointestinal disturbances) were sim-
ilar between treatment groups.
Comment: The RCTs used pain scales as the basis of randomised allocation. This method of randomisation
may introduce bias.
OPTION PARACETAMOL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
We found no direct information from RCTs about the effects of paracetamol (acetaminophen) on pain in
people with sickle cell crisis.

Paracetamol is widely used by clinicians to relieve mild pain and fever. Standard clinical dosage
of paracetamol is well tolerated and unlikely to cause harm, but overdose is known to cause liver
toxicity (see review on paracetamol [acetaminophen] poisoning).
OPTION CORTICOSTEROIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Dexamethasone plus morphine compared with placebo We don’t know whether intravenous dexamethasone given
as an adjunct to narcotic analgesia is more effective at reducing pain in people with acute sickle cell episodes (very
low-quality evidence).
Methylprednisolone plus morphine compared with placebo plus morphine We don’t know whether high-dose intra-
venous methylprednisolone given as an adjunct to narcotic analgesia is more effective at reducing pain in people
with acute episodes of severe sickle cell crisis (low-quality evidence).
Adverse effects
Corticosteroids have been associated with adverse effects, such as increased risk of infections, weight gain, hyper-
tension, poor glucose metabolism, cataracts, and poor growth in children.
For GRADE evaluation of interventions in sickle cell disease see table, p 19 .

[42]
Benefits: We found one systematic review (search date 2002, 3 RCTs, 148 people) comparing corticos-
teroids plus narcotic analgesics versus placebo plus narcotic analgesics. Due to heterogeneity of
methodologies and reporting, the review did not perform a meta-analyses. We therefore comment
on all studies of sufficient quality individually below. We also found one additional RCT (38 children,
[48]
median age 6.7 years), which compared dexamethasone versus placebo.
Dexamethasone plus morphine versus placebo plus morphine:

One RCT included in the review (80 people randomised by sickle cell episodes, total of 152 acute
sickle cell episodes) compared 2 days of parenteral dexamethasone (0.3 mg/kg/dose x 4 doses)
[49]
versus placebo (saline) as an adjunct to analgesia. The RCT found a significant reduction in
the duration of analgesia therapy with dexamethasone compared with placebo (36.2 hours with
[49]
dexamethasone v 48.4 hours with placebo; P = 0.04, CI not reported). The additional RCT
compared intravenous dexamethasone versus placebo, given as an adjunct to narcotic analgesia
(intravenous morphine followed by oral codeine plus paracetamol) in 43 episodes of acute chest
syndrome (34 children aged 1–13 years randomised on an individual level). It found that dexam-
ethasone significantly reduced the need for analgesia when compared with placebo (mean number
of analgesic doses: 2.5 with dexamethasone v 20.0 with placebo; P less than 0.001; mean duration
of analgesic doses: 16.8 hours with dexamethasone v 76.8 hours with placebo; P less than 0.001).
[48]

Sickle cell disease
Methylprednisolone plus morphine versus placebo plus morphine:
[42]
The systematic review identified one RCT comparing high-dose intravenous methylprednisolone
versus placebo, given as an adjunct to narcotic analgesia (iv morphine followed by oral codeine
plus paracetamol) in 56 acute episodes of severe painful sickle cell crisis in 34 people aged 2–19
[50]
years. Pain episodes were the basis for randomisation. It found that methylprednisolone signif-
icantly reduced the duration of inpatient analgesia (iv or oral) compared with placebo (41.3 hours
with methylprednisolone v 71.3 hours with placebo; P = 0.01). It found no significant difference
between methylprednisolone and placebo in readmissions to hospital for recurrent pain within 2
weeks, although more people taking methylprednisolone were readmitted (4/26 [15%] with
methylprednisolone v 1/30 [3%] with placebo; RR 4.62, 95% CI 0.55 to 38.74). The RCT may have
lacked power to rule out a clinically important difference between groups.
Harms: Dexamethasone plus morphine versus placebo plus morphine:

[42]
The review gave no information on adverse effects. Some known adverse effects of corticos-
teroids are increased risk of infections, weight gain, hypertension, poor glucose metabolism,
cataracts, and poor growth in children.
Methylprednisolone plus morphine versus placebo plus morphine:

[42]
One RCT in the systematic review found no adverse effects associated with methylprednisolone.
[50]
Comment: The RCTs used pain scales as the basis of randomised allocation. This method of randomisation
may introduce bias.
OPTION MORPHINE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Oral morphine compared with intravenous morphine Controlled-release oral morphine (given after an intravenous
loading dose of morphine at onset of treatment) and intravenous morphine are equally effective at reducing pain,
and the duration of pain in children with vaso-occlusive crisis (moderate-quality evidence).
Adverse effects
Controlled-release oral morphine has been associated with an increased risk of acute chest syndrome in people with
sickle cell crisis.
Benefits: Morphine versus placebo:

We found no systematic review or RCTs.
Oral versus intravenous morphine:

We found one RCT (56 children, aged 5–17 years with painful crisis) comparing controlled-release
morphine given orally (1.9 mg/kg every 12 hours) plus intravenous placebo (saline) versus intra-
[51]
venous morphine (0.04 mg/kg) plus placebo tablets for sickle cell vaso-occlusive crisis. All
children were given an intravenous loading dose of morphine (0.15 mg/kg) at the onset of treatment.
The RCT found that the oral medication was as effective as the intravenous injection. There was
no significant difference in pain assessed by the Children’s Hospital of Eastern Ontario Pain Scale
(CHEOPS) (WMD +0.10 units, 95% CI –0.09 units to +0.70 units) or other clinical pain scales
(Oucher, faces, or clinical pain scales: –0.20 units, 95% CI –0.54 units to +0.14 units) throughout
the observation period (at 09:00, 13:00, 17:00, and 21:00 hours every day). It also found no signif-
icant difference between oral and intravenous morphine in the mean frequency of rescue analgesia
(WMD –0.12 doses/day, 95% CI –0.30 doses/day to +0.06 doses/day) and the mean duration of
pain (WMD +1.20 days, 95% CI –0.01 days to +2.41 days).
Harms: Oral morphine versus intravenous morphine:

The RCT found no significant difference in the frequency of spontaneously reported adverse events
(62% with oral morphine v 52% with iv morphine) or severe-intensity events (16% with oral morphine
v 19% with iv morphine; no further significance assessment reported) between oral and intravenous
morphine. Common adverse events were fever, pruritus, nausea, vomiting, and constipation; these
[51]
did not differ significantly between study groups. A post hoc analysis of the same RCT found
that oral morphine increased the risk of acute chest syndrome compared with intravenous morphine
(AR: 12/21 [57%] with oral morphine v 4/23 [17%] with iv morphine; P less than 0.001; see comment
[52]
below).
Comment: In the post hoc analysis of the RCT, children with acute chest syndrome at enrolment were excluded.
[52]

Sickle cell disease
GLOSSARY
Aplastic crisis Sudden cessation of the bone marrow from making new blood cells.
CHEOPS scale (Children's Hospital of Eastern Ontario Pain scale) A behavioural scale used to evaluate postop-
erative pain. It was initially validated in children aged 1–5 years, and subsequently validated in children from other
[54]
populations and ages. The CHEOPS scale is used to monitor the effectiveness of interventions for reducing pain
and discomfort. Scores obtained from adding points from six different parameters range from 4 to 13.
Dactylitis Inflammation of the bones of the hands and feet, resulting in swelling, redness, and pain in the affected
parts. It is common in young infants with sickle cell disease, and is precipitated by the sickle process that characterises
sickle cell disease. Because it tends to occur bilaterally in the hands and feet with swelling of the dorsum, it is com-
monly described as sickle cell “hand and foot syndrome”.
Fetal haemoglobin (Hb F) This is the predominant type of normal haemoglobin (i.e. the oxygen carrying molecule
in the human red blood cell) in the unborn child. Following birth, another type of normal haemoglobin (Hb A) replaces
Hb F and remains predominant throughout life. Hb F binds oxygen more strongly than Hb A and maintains higher
tissue oxygen tension than Hb A.
Pneumococcal conjugate vaccines These are polysaccharide pneumococcal vaccines linked with proteins such
as those of the outer membrane of meningococcus, or tetanus, or diphtheria toxoids. The conjugate pneumococcal
vaccines have been shown to be immunogenic in children younger than 2 years, and are recommended for routine
[29] [53]
use in infants beginning from the age of 2 months.
Sequestration crisis Sudden pooling of blood in the spleen and liver, with the result that the person becomes
anaemic and hypotensive, with the affected organ becoming remarkably enlarged and painful.
Acute chest syndrome Acute chest syndrome is a life-threatening complication of sickle cell disease characterised
by fever, cough, chest pain, difficulty in breathing, worsening anaemia, and new pulmonary infiltrates on radiography.
It is difficult to differentiate acute chest syndrome clinically from pneumonia and pulmonary infarctions.
High-quality evidence Further research is very unlikely to change our confidence in the estimate of effect.
Low-quality evidence Further research is very likely to have an important impact on our confidence in the estimate
of effect and is likely to change the estimate.
Moderate-quality evidence Further research is likely to have an important impact on our confidence in the estimate
of effect and may change the estimate.
Polyvalent polysaccharide pneumococcal vaccine (PPV) This type of vaccine contains the purified capsular
polysaccharides of several Streptococcus pneumoniae serotypes. Many of the polysaccharides contained in the
vaccines do not induce protective immunity in children younger than 2 years. This type of pneumococcal vaccine is
recommended for children aged 2 years and older affected by conditions that predispose them to an increased risk
[53]
of invasive pneumococcal infection.
Very low-quality evidence Any estimate of effect is very uncertain.
SUBSTANTIVE CHANGES
Blood transfusion (prophylactic) sickle cell disease New option for which we found one systematic review iden-
[15]
tifying two RCTs. The review found that prophylactic blood transfusion significantly reduced the rate of stroke
compared with standard care or no transfusion at 16–24 months. Categorised as a Trade-off between benefits and
harms.
Corticosteroids for sickle cell disease One systematic review added comparing corticosteroids plus morphine
[42]
versus placebo plus morphine. One RCT included in the review found a significant reduction in the duration of
analgesia with dexamethasone compared with placebo. Another RCT included in the review found that methylpred-
[42]
nisolone significantly reduced the duration of inpatient analgesia compared with placebo. Categorisation unchanged
(Trade-off between benefits and harms).
[42]
Diflunisal for sickle cell disease One systematic review added comparing diflunisal versus placebo. The review
found no significant difference between groups for pain intensity. Categorisation unchanged (Unknown-effectiveness).
[30]
Hydration for sickle cell disease We found one systematic review that identified no RCTs. Categorisation un-
changed (Unknown effectiveness).
Ketorolac for sickle cell disease One systematic review added comparing ketorolac versus placebo, ketorolac
plus pethidine versus placebo plus pethidine, or ketorolac plus morphine sulphate versus placebo plus morphine
[42]
sulphate. One RCT included in the review found that ketorolac significantly reduced pain compared with pethidine
at 30 minutes, but had no significant difference between groups at 150 minutes. Two RCTs included in the review
found that ketorolac plus pethidine did not significantly reduce pain compared with placebo plus pethidine. One RCT
included in the review found no significant difference in the need for morphine between ketorolac compared with
placebo. Categorisation unchanged (Unknown effectiveness).
Zinc sulphate for preventing sickle cell disease We found one systematic review comparing zinc sulphate versus
[27]
placebo. The review found that zinc sulphate significantly decreased the number of sickle cell crises compared
with placebo. Categorisation unchanged (Likely to be beneficial).
[25]
Piracetam for sickle cell disease We found one systematic review comparing piracetam versus placebo. The
review included three RCTs, but only one was reported fully. This RCT found that piracetam significantly reduced
the incidence of sickle cell crisis compared with placebo. Categorisation changed from Likely to be beneficial to Un-
known effectiveness.
REFERENCES
Sickle cell disease
1. Akinyanju OO. A profile of sickle cell disease in Nigeria. Ann N Y Acad Sci books of conference proceedings, and contact with relevant pharmaceutical
1989;565:126–136.[PubMed] companies and experts in the field.
2. Serjeant GR. Sickle cell disease, 2nd rev ed. Oxford: Oxford University Press, 29. Pai VB, Heyman CA, Erramouspe J, et al. Conjugated heptavalent pneumococcal
1992. vaccine. Ann Pharmacother 2002;36:1403–1413.[PubMed]
3. Ohene-Frempong K, Nkrumah FK. Sickle cell disease in Africa. In: Embury SH, 30. Okomo U, Meremikwu MM. Fluid replacement therapy for acute episodes of pain
Hebbel RP, Mohandas N, et al, eds. Sickle cell disease: basic principles and in people with sickle cell disease. In: The Cochrane Library, Issue 2, 2007.
clinical practice. New York: Raven Press Ltd, 1994. Chichester, UK: John Wiley & Sons Ltd. Search date 2007; primary sources
4. Hickman M, Modell B, Greengross P, et al. Mapping the prevalence of sickle cell Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, which
and beta thalassaemia in England: estimating and validating ethnic-specific rates. comprises of references identified from comprehensive electronic database
Br J Haematol 1999;104:860–867.[PubMed] searches and hand searches of relevant journals and abstract books of conference
proceedings.[PubMed]
5. Davies SC, Oni L. Management of patients with sickle cell disease. BMJ
1997;315:656–660.[PubMed] 31. Robieux IC, Kellner JD, Coppes MJ, et al. Analgesia in children with sickle cell
crisis: comparison of intermittent opioids vs. continuous intravenous infusion of
6. Effiong CE. Sickle cell disease in childhood. In: Fleming AF, ed. Sickle cell dis-
morphine and placebo-controlled study of oxygen inhalation. Pediatr Hematol
ease: a handbook for general clinicians. Edinburgh: Churchill Livingstone,
Oncol 1992;9:317–326.[PubMed]
1982:57–72.
32. Zipursky A, Robieux IC, Brown EJ, et al. Oxygen therapy in sickle cell disease.
7. Overturf GD, Powars D, Baraff LJ. Bacterial meningitis and septicemia in sickle
Am J Pediatr Hematol Oncol 1992;14:222–228.[PubMed]
cell disease. Am J Dis Child 1977;131:784–787.[PubMed]
33. Hirst C, Williamson L. Preoperative blood transfusions for sickle cell disease. In:
8. Cohen AR, Norris CF, Smith-Whitley K. Transfusion therapy for sickle cell disease.
The Cochrane Library, Issue 3, 2007. Chichester, UK: John Wiley & Sons Ltd.
In: Capon SM, Chambers LA, eds. New directions in pediatric hematology.
Search date 2007; primary sources Cochrane Cystic Fibrosis and Genetic Disor-
Bethesda, MD: American Association of Blood Banks, 1996:39–85.
ders Group Trials Register which comprises references identified from compre-
9. Adams R, McKie V, Nichols F, et al. The use of transcranial ultrasonography to hensive electronic database searches, hand searches of relevant journals and
predict stroke in sickle cell disease. N Engl J Med 1992;326:605–610. [PubMed] abstract books of conference proceedings.
10. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease: life ex- 34. Telen MJ. Principles and problems of transfusion in sickle cell disease. Semin
pectancy and risk factors for early death. N Engl J Med Hematol 2001;38:315–323.[PubMed]
1994;330:1639–1643.[PubMed]
35. Hirst C, Wang WC. Blood transfusion for preventing stroke in people with sickle
11. Harmatz P, Butensky E, Quirolo K, et al. Severity of iron overload in patients with cell disease. In: The Cochrane Library, Issue 3, 2007. Chichester, UK: John Wiley
sickle cell disease receiving chronic red blood cell transfusion therapy. Blood & Sons Ltd. Search date 2006; primary sources Cochrane Cystic Fibrosis and
2000;96:76–79.[PubMed] Genetic Disorders Group Trials Register, comprising references identified from
12. Redwood AM, Williams EM, Desal P, et al. Climate and painful crisis of sickle- comprehensive electronic database searches and hand searches of relevant
cell disease in Jamaica. BMJ 1976;1:66–68.[PubMed] journals and conference proceedings.
13. Mohan J, Marshall JM, Reid HL, et al. Peripheral vascular response to mild indirect 36. Emre U, Miller ST, Gtierez M, et al. Effect of transfusion in acute chest syndrome
cooling in patients with homozygous sickle cell (SS) disease and the frequency of sickle cell disease. J Pediatr 1995;127:901–904.[PubMed]
of painful crisis. Clin Sci 1998;94:111–120.[PubMed] 37. Talano JM, Hillery CA, Gottschall JL, et al. Delayed hemolytic transfusion reac-
14. Saborio P, Scheinman JI. Sickle cell nephropathy. J Am Soc Nephrol tion/hyperhemolysis syndrome in children with sickle cell disease. Pediatrics
1999;10:187–192.[PubMed] 2003;111:e661–e665.[PubMed]
15. Riddington C, Wang WC. Blood transfusion for preventing stroke in people with 38. Perlin E, Finke H, Castro O, et al. Infusional/patient-controlled analgesia in sickle-
sickle cell disease. In: The Cochrane Library, Issue 1, 2002. Chichester, UK: cell vaso-occlusive crises. Pain Clinic 1993;6:113–119.
John Wiley & Sons Ltd. Search date 2006.[PubMed] 39. Gonzalez ER, Bahal N, Hansen LA, et al. Intermittent injection vs patient-controlled
16. Adams RJ, McKie VC, Brambilla D, et al. Stroke prevention trial in sickle cell analgesia for sickle cell crises pain: comparison in patients in the emergency
anemia. Control Clin Trials 1998;19:110–129.[PubMed] department. Arch Intern Med 1991;151:1373–1378.[PubMed]
17. Adams RJ, Brambilla D, Optimizing Primary Stroke Prevention in Sickle Cell 40. Hagmeyer KO, Mauro LS, Mauro VF. Meperidine-related seizures associated
Anemia (STOP 2) Trial Investigators. Discontinuing prophylactic transfusions with patient-controlled analgesia pumps. Ann Pharmacother
used to prevent stroke in sickle cell disease. N Engl J Med 1993;27:29–33.[PubMed]
2005;353:2769–2778.[PubMed] 41. Shapiro BS, Ballas SK. The acute painful episode. In: Embury SH, Hebbel RP,
18. Hirst C, Owusu-Ofori S. Prophylactic antibiotics for preventing pneumococcal Mohandas N, et al, eds. Sickle cell disease: principles and clinical practice. New
infection in children with sickle cell disease. In: The Cochrane Library, Issue 3, York: Raven Press Ltd, 1994.
2006. Chichester, UK: John Wiley & Sons Ltd. Search date 2005; primary sources 42. Dunlop RJ, Bennett KC. Pain management for sickle cell disease. In: The
Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Cochrane Library, Issue 2, 2006. Chichester, UK: John Wiley & Sons Ltd. Search
Trials Register, references identified from comprehensive electronic database date 2002.[PubMed]
searches, and hand searches of relevant journals and abstract books of confer-
43. Perlin E, Finke H, Castro O, et al. Treatment of sickle cell pain crisis: a clinical
ence proceedings.
trial of diflunisal (Dolobid). Clin Trials J 1988;25:254–264.
19. Overturf GD. Pneumococcal vaccination of children. Semin Pediatr Infect Dis
44. Grisham JE, Vichinsky EP. Ketorolac versus meperidine in vaso-occlusive crisis:
2002;13:155–164.[PubMed]
a study of safety and efficacy. Int J Pediatr Hematol Oncol 1996;3:239–247.
20. Falletta JM, Woods GM, Verter JI, et al. Discontinuing penicillin prophylaxis in
45. Wright SW, Norris RL, Mitchell TR. Ketorolac for sickle cell vaso-occlusive crisis
children with sickle cell anemia. J Pediatr 1995;127:685–690.[PubMed]
pain in the emergency department: lack of a narcotic-sparing effect. Ann Emerg
21. Davies S, Olujohungbe A. Hydroxyurea for sickle cell disease. In: The Cochrane Med 1992;21:925–928.[PubMed]
Library, Issue 3, 2006. Chichester, UK: John Wiley & Sons Ltd. Search date
46. Perlin E, Finke H, Castro O, et al. Enhancement of pain control with ketorolac
2004.
tromethamine in patients with sickle cell vaso-occlusive crisis. Am J Hematol
22. Ferster A, Vermylen C, Cornu G, et al. Hydroxyurea for treatment of severe 1994;46:43–47.[PubMed]
sickle cell anemia: a pediatric clinical trial. Blood 1996;88:1960–1964.[PubMed]
47. Hardwick WE, Givens TG, Monroe KW, et al. Effect of ketorolac in pediatric
23. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency sickle cell vaso-occlusive pain crisis. Pediatr Emerg Care
of painful crisis in sickle cell anemia. N Engl J Med 1995;332:1317–1322.[PubMed] 1999;15:179–182.[PubMed]
24. Oniyangi O, Omari AAA. Malaria chemoprophylaxis in sickle cell disease. In: The 48. Bernini JC, Rogers ZR, Sandler ES, et al. Beneficial effect of intravenous dexam-
Cochrane Library, Issue 4, 2006. Chichester, UK: John Wiley & Sons Ltd. Search ethasone in children with mild to moderately severe acute chest syndrome com-
date 2006; primary sources Cochrane Infectious Diseases Group Specialized plicating sickle cell disease. Blood 1998;92:3082–3089.[PubMed]
Register, Cochrane Cystic Fibrosis and Genetic Disorders Group Specialized
49. Rogers ZR, Dale JC, Bernini JC, et al. Dexamethasone shortens the duration of
Register, Central (The Cochrane Library), Medline, Embase, Liliacs, and reference
painful events requiring hospitalisation in children with sickle cell disease: results
lists.
of a randomized double-blind placebo-controlled trial. Blood 1995;86:250a.
25. Al Hajeri A, Fedorowicz Z, Omran A, et al. Piracetam for reducing the incidence
50. Griffin TC, McIntire D, Buchanan GR. High-dose intravenous methylprednisolone
of painful sickle cell disease crises. In: The Cochrane Library, Issue 2, 2007.
therapy for pain in children and adolescents with sickle cell disease. N Engl J
Chichester, UK: John Wiley & Sons, Ltd. Search date 2007; primary sources
Med 1994;330:733–737.[PubMed]
Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies
Trials Register which comprises of references identified from comprehensive 51. Jacobson SJ, Kopecky EA, Joshi P, et al. Randomised trial of oral morphine for
electronic database searches and hand searches of relevant journals and abstract painful episodes of sickle-cell disease in children. Lancet
books of conference proceedings.[PubMed] 1997;350:1358–1361.[PubMed]
26. Mikati MA, Solh HM, Deryan DE, et al. A preliminary report on piracetam in 52. Kopecky EA, Jacobson S, Joshi P, et al. Systematic exposure to morphine and
sickle cell anemia: a double-blind crossover clinical trial and effects on erythrocyte the risk of acute chest syndrome in sickle cell disease. Clin Pharmacol Ther
survival. King Faisal Spec Hosp Med J 1983;3:233–236. 2004;75:140–146.[PubMed]
27. Singh PC, Ballas SK. Drugs for preventing red blood cell dehydration in people 53. Overturf GD. American Academy of Pediatrics. Technical report: prevention of
with sickle cell disease. In: The Cochrane Library, Issue 4, 2007. Chichester, pneumococcal infections, including the use of pneumococcal conjugate and
UK: John Wiley & Sons Ltd. Search date 2006. polysaccharide vaccines and antibiotic prophylaxis. Pediatrics
2000;106:367–376.[PubMed]
28. Davies EG, Riddington C, Lottenberg R, et al. Pneumococcal vaccines for sickle
cell disease. In: The Cochrane Library, Issue 3, 2006. Chichester, UK: John Wiley 54. Suraseranivongse S, Santawat U, Kraiprasit K, et al. Cross-validation of a com-
& Sons Ltd. Search date 2004; primary sources Cochrane Cystic Fibrosis and posite pain scale for preschool children within 24 hours of surgery. Br J Anaesth
Genetic Disorders Group Trials Register, references identified from comprehensive 2001;87:400–405. [PubMed]
electronic database searches, hand searches of relevant journals and abstract

Sickle cell disease
Martin M Meremikwu
Department of Paediatrics
College of Medical Sciences, University of Calabar
Calabar
Nigeria
Competing interests: MM declares that he has no competing interests.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a
judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and
harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices.
Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research
we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the
categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately
it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest
extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any
person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, inci-
dental or consequential, resulting from the application of the information in this publication.

Sickle cell disease
TABLE GRADE evaluation of interventions for sickle cell disease
Important out-
comes Incidence of crises, disease-related complications, symptom severity (pain), quality of life, mortality, adverse effects
Type of
Number of stud- evi- Consis- Direct- Effect
ies (participants) Outcome Comparison dence Quality tency ness size GRADE Comment
What are the effects of non-pharmaceutical interventions to prevent sickle cell crisis and other acute complications in people with sickle cell disease?
[15]
2 (209) Disease-related compli- Blood transfusion (prophylactic) 4 0 0 0 +1 High Effect-size point added for OR less than 0.5
cations v standard care or no treatment
[15]
2 (209) Mortality Blood transfusion (prophylactic) 4 0 0 0 0 High
v standard care or no treatment
What are the effects of pharmaceutical interventions to prevent sickle cell crisis and other acute complications in people with sickle cell disease?
[18]
2 (457) Disease-related compli- Penicillin v placebo (children un- 4 0 0 –1 +1 High Directness point deducted for differences in
cations der 5 years of age) vaccination status of children. Effect size point
added for RR less than 0.5
[18]
2 (215) Mortality Penicillin v placebo (children un- 4 –1 0 0 0 Moderate Quality point deducted for low event rates
der 5 years of age)
[18]
1 (400) Disease-related compli- Penicillin v placebo (children over 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting
cations 5 years of age) of results
[18]
2 (215) Mortality Penicillin v placebo (children un- 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting
der 5 years of age) of results
[21]
1 (299) Incidence of crises Hydroxyurea v placebo 4 0 0 0 0 High
[21]
1 (299) Disease-related compli- Hydroxyurea v placebo 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting
cations of results
[21]
1 (299) Mortality Hydroxyurea v placebo 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting
of results
[21]
1 (299) Quality of life Hydroxyurea v placebo 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting
of results
[24]
1 (97) Incidence of crises Malaria chemoprophylaxis v 4 –1 0 –1 +1 Moderate Quality point deducted for sparse data. Direct-
placebo ness point deducted for uncertainty about gen-
eralisability of regimens used for prophylaxis.
Effect size point added for RR less than 0.5
[24]
1 (97) Disease-related compli- Malaria chemoprophylaxis v 4 –1 0 0 0 Moderate Quality point deducted for sparse data
cations placebo
[24]
1 (157) Disease-related compli- Malaria chemoprophylaxis plus 4 –2 0 –1 0 Very low Quality points deducted for sparse data and
cations antibiotic v placebo randomisation/allocation flaws. Consistency
point deducted for conflicting results. Directness
point deducted for uncertainty about generalis-
ability of regimens used for prophylaxis
[25]
3 (169) Incidence of crises Piracetam v placebo 4 –2 –1 0 0 Very low Quality points deducted for sparse data and in-
complete reporting of results. Consistency point
deducted for lack of agreement between studies
© BMJ Publishing Group Ltd 2009. All rights reserved. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Sickle cell disease
Important out-
comes Incidence of crises, disease-related complications, symptom severity (pain), quality of life, mortality, adverse effects
Type of
Number of stud- evi- Consis- Direct- Effect
ies (participants) Outcome Comparison dence Quality tency ness size GRADE Comment
[27]
1 (145) Incidence of crises Zinc sulphate v placebo 4 –1 0 –1 0 Low Quality point deducted for sparse data. Direct-
ness point deducted for uncertainty about results
because of small size of RCT
[28]
1 (242) Disease-related compli- Polysaccharide pneumococcal 4 0 0 0 0 High
cations vaccine v control
What are the effects of non-pharmaceutical interventions to treat pain in people with sickle cell crisis?
[31]
1 (50) Symptom severity (pain) Oxygen v air 4 –2 0 0 0 Low Quality points deducted for sparse data and in-
complete reporting of results
What are the effects of pharmaceutical interventions to treat pain in people with sickle cell crisis?
[38]
1 (20) Symptom severity (pain) Patient-controlled pethidine v in- 4 –2 0 0 0 Low Quality points deducted for sparse data and
termittently administered pethi- uncertainty about method of evaluating pain
dine
[39]
1 (45) Symptom severity (pain) Patient-controlled morphine v in- 4 –1 0 0 0 Moderate Quality point deducted for sparse data
termittently administered mor-
phine
[42]
1 (37) Symptom severity (pain) Diflunisal v placebo 4 –3 0 0 0 Very low Quality points deducted for sparse data, incom-
plete reporting of results, and randomisation/al-
location flaws
[42] [44]
1 (20) Symptom severity (pain) Ketorolac v pethidine 4 –2 –1 0 0 Very low Quality points deducted for sparse data and
randomisation/allocation flaws. Consistency
point deducted for different results at different
endpoints
[42] [45]
2 (39) Symptom severity (pain) Ketorolac plus pethidine v place- 4 –2 –1 0 0 Very low Quality points deducted for sparse data and
[46]
bo plus pethidine randomisation/allocation flaws. Consistency
point deducted for assessing different outcomes
and for lack of agreement between studies
[42] [47]
1 (29) Symptom severity (pain) Ketorolac plus morphine sulphate 4 –2 0 0 0 Low Quality points deducted for sparse data and
v placebo plus morphine sulphate randomisation/allocation flaws
[49] [48]
2 (114) Symptom severity (pain) Dexamethasone plus morphine v 4 –2 0 –1 0 Very low Quality points deducted for sparse data and
placebo randomisation/allocation flaws. Directness point
deducted for not assessing pain reduction
[42] [50]
1 (34) Symptom severity (pain) Methylprednisolone plus mor- 4 –2 0 0 0 Low Quality points deducted for sparse data and
phine v placebo randomisation/allocation flaws
[51]
1 (86) Symptom severity (pain) Oral morphine v intravenous 4 –1 0 0 0 Moderate Quality point deducted for sparse data
morphine
Type of evidence: 4 = RCT; 2 = Observational;
Consistency: similarity of results across studies
Directness: generalisability of population or outcomes
Effect size: based on relative risk or odds ratio
© BMJ Publishing Group Ltd 2009. All rights reserved. ............................................................................................................ 20

Sickle Cell Disease: Martin M Meremikwu

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Sickle Cell Disease: Martin M Meremikwu

Uploaded by

Copyright:

Available Formats

Blood and lymph disorders

Sickle cell disease

Treatment of chronic ulcers Treatments for sickle cell disease in pregnancy

© BMJ Publishing Group Ltd 2009. All rights reserved. ........................................................... 2

OPTION AVOIDANCE OF COLD ENVIRONMENT. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Benefits: We found no systematic review, RCTs, or observational studies of sufficient quality.

Harms: We found no RCTs or observational studies.

© BMJ Publishing Group Ltd 2009. All rights reserved. ........................................................... 3

OPTION LIMITING PHYSICAL EXERCISE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Benefits: We found no systematic review, RCTs, or observational studies of sufficient quality.

Harms: We found no RCTs or observational studies.

Comment: Clinical guide:

Harms: We found no RCTs.

OPTION BLOOD TRANSFUSION (PROPHYLACTIC) FOR SICKLE CELL CRISIS . . . . . . . . . . . . . New

© BMJ Publishing Group Ltd 2009. All rights reserved. ........................................................... 4

OPTION ANTIBIOTIC PROPHYLAXIS IN CHILDREN UNDER 5 YEARS OF AGE. . . . . . . . . . . . . . . . . . .

© BMJ Publishing Group Ltd 2009. All rights reserved. ........................................................... 5

OPTION ANTIBIOTIC PROPHYLAXIS IN CHILDREN OVER 5 YEARS OF AGE. . . . . . . . . . . . . . . . . . . .

Comment: Clinical guide:

Benefits: Hydroxyurea versus placebo:

OPTION MALARIA CHEMOPROPHYLAXIS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Benefits: Malaria chemoprophylaxis versus placebo:

© BMJ Publishing Group Ltd 2009. All rights reserved. ........................................................... 7

Comment: Clinical guide:

OPTION ZINC SULPHATE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

© BMJ Publishing Group Ltd 2009. All rights reserved. ........................................................... 8

OPTION PNEUMOCOCCAL VACCINES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Benefits: Polysaccharide pneumococcal vaccine versus placebo:

Pneumococcal conjugate vaccine versus placebo:

Comment: Clinical guide:

Benefits: We found no systematic review or RCTs.

© BMJ Publishing Group Ltd 2009. All rights reserved. ........................................................... 9

Comment: Clinical guide:

Symptom severity (pain)

Benefits: Oxygen versus air:

Harms: Oxygen versus air:

OPTION BLOOD TRANSFUSION FOR SICKLE CELL PAIN. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Harms: We found no RCTs.

OPTION PATIENT-CONTROLLED ANALGESIA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Symptom severity (pain)

Benefits: Patient-controlled pethidine versus intermittently administered pethidine:

Patient-controlled morphine versus intermittently administered morphine:

Harms: Patient-controlled pethidine versus intermittently administered pethidine:

Patient-controlled morphine versus intermittently administered morphine:

© BMJ Publishing Group Ltd 2009. All rights reserved. .......................................................... 11

Benefits: We found no systematic review or RCTs.

Harms: We found no RCTs.

Comment: Clinical guide:

Benefits: We found no systematic review or RCTs.

Symptom severity (pain)

Benefits: Oral diflunisal versus placebo:

Harms: Oral diflunisal versus placebo:

© BMJ Publishing Group Ltd 2009. All rights reserved. .......................................................... 12

Benefits: We found no systematic review or RCTs.

Symptom severity (pain)

Ketorolac versus pethidine:

Ketorolac plus pethidine versus placebo plus pethidine:

Ketorolac plus morphine sulphate versus placebo plus morphine sulphate:

Benefits: We found no systematic review or RCTs.

Harms: We found no RCTs.

Comment: Clinical guide:

Symptom severity (pain)

For GRADE evaluation of interventions in sickle cell disease see table, p 19 .